Download MendeleyNew 7-Methyl-Guanosine Derivatives Targeting the Influenza Polymerase Pb2 CAP-Binding Domain
Pautus, S., Sehr, P., Lewis, J., Fortune, A., Wolkerstorfer, A., Szolar, O., Gulligay, D., Lunardi, T., Decout, J.L., Cusack, S.(2013) J Med Chem 56: 8915
- PubMed: 24134208
- DOI: https://doi.org/10.1021/jm401369y
- Primary Citation of Related Structures:
4CB4, 4CB5, 4CB6, 4CB7 - PubMed Abstract:
The heterotrimeric influenza virus polymerase performs replication and transcription of viral RNA in the nucleus of infected cells. Transcription by "cap-snatching" requires that host-cell pre-mRNAs are bound via their 5' cap to the PB2 subunit. Thus, the PB2 cap-binding site is potentially a good target for new antiviral drugs that will directly inhibit viral replication. Docking studies using the structure of the PB2 cap-binding domain suggested that 7-alkylguanine derivatives substituted at position N-9 and N-2 could be good candidates. Four series of 7,9-di- and 2,7,9-trialkyl guanine derivatives were synthesized and evaluated by an AlphaScreen assay in competition with a biotinylated cap analogue. Three synthesized compounds display potent in vitro activity with IC50 values lower than 10 ¦̀M. High-resolution X-ray structures of three inhibitors in complex with the H5N1 PB2 cap-binding domain confirmed the binding mode and provide detailed information for further compound optimization.
Organizational Affiliation:
D¨¦partement de Pharmacochimie Mol¨¦culaire, Universit¨¦ de Grenoble Alpes/CNRS, UMR 5063 , ICMG FR 2607, 470 rue de la Chimie, BP 53, F-38041 Grenoble, France.
